| Summary: | 碩士 === 國立中山大學 === 生物醫學研究所 === 104 === Hepatoma-derived growth factor (HDGF) is a mitogen of 240 residues involved in hepatocarcinogenesis. HDGF consists of a highly conserved PWWP domain in the N-terminal 100 residues and the C140 domain with a nuclear localization signal (NLS) that located in C140 domain and PWWP domain respectively. Moreover, the Ser-103 phosphorylation site is necessary for mitogenic activity of HDGF. Studies have shown that HDGF expression and ROS levels increase as HCC progression from Grade Ι to Grade III in HCC patients. Additionally, the interaction of HDGF and nucleolin also promotes liver carcinogenesis. Therefore, we want to investigate the correlation between HDGF and ROS generation in hepatocellular carcinoma. In this study, we found that wild type HDGF protein, C140 domain and S103E protein enhanced ROS production, proliferation and invasion of SK-Hep-1 hepatoma cells. However, the effect of PWWP domain and S103A mutant of HDGF on inducing cell proliferation, invasion and ROS generation was weaker than C140 domain and S103E mutant of HDGF. Blocking ROS generation by NAC attenuated HDGF-induced cell growth and invasion. We further clarified that the function of HDGF protein and C140 domain could be blocked by neutralizing the cell surface dominant receptor nucleolin (NCL), but the capacity for blockage of S103E activity was diminished. Up-regulation of SOD1, SOD2, MFN2 and PGC1α as well as down-regulation of FIS-1 and DRP-1 suggested that HDGF-induced ROS might increase antioxidant proteins to detoxify from the elevated ROS and stimulate mitochondrial biogenesis in HCC. In conclusion, we demonstrated that HDGF-induced mitochondrial ROS generation provoked liver cancer progression.
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